Characterising brain network differences during scene perception and memory in young adult APOE-e4 carriers: multi-modal imaging in ALSPAC

英国大约有85万人患有痴呆症；到2025年，这一数字将增加到100多万，到2050年预计将超过200万。神经退行性疾病每年给英国经济带来的财务成本超过240亿英镑，而且还在上升；然而，将痴呆症的发病推迟5年就可以将这些费用减少一半。因此，越早实施潜在的干预措施，对改善健康的好处就越大，减少痴呆症的经济和社会负担的机会也就越大。了解何时以及对谁实施预防性干预的关键是在与年龄相关的认知衰退开始之前识别高危个体。在这里，我们认为晚年认知健康状况较差的“脆弱性”并不仅仅与“衰老”有关，而是与整个生命周期中风险的积累有关。这一说法预测，晚年生活中明显的一些认知和大脑差异可以通过早期生活因素来预测，并有助于研究年轻健康个体，这些个体由于拥有与衰老认知障碍相关的基因而面临与年龄相关的认知能力下降的高风险。在本研究计划中，我们将重点关注一种常见的半显性风险等位基因APOE-e4的潜在影响，通过询问：(a)健康的APOE-e4携带者在成年早期是否表现出与有害衰老的早期认知和解剖标记相一致的选择性大脑和行为差异（与非携带者相比），以及(b)这种早期生活影响如何被认知储备、性别和生活方式因素所调节。一项大规模的神经影像学研究将在来自雅芳父母和儿童纵向研究（ALSPAC）队列的年轻人中进行，包括7T MRI的新应用，它可以详细评估内侧颞叶（如海马）的关键大脑结构。这种方法是建立在年轻APOE e4携带者早期大脑网络变化（特别是在场景感知和记忆期间）的强有力的试点证据基础上的，它将确定年轻高危个体在何种情况下会出现这种认知变化，询问这些大脑网络变化是否与行为表现（例如，成功的感知和记忆）有关，并确定这种早期生活认知脆弱性如何被性别所缓和。生活方式和认知储备。

Approximately 850,000 people in the UK have dementia; by 2025, this will increase to over one million, and by 2050 is projected to exceed 2 million. The annual financial cost of neurodegenerative disease to the UK economy is over £24 billion and rising; yet delaying dementia onset by just 5 years could reduce these costs by half. The earlier that potential interventions can be implemented, therefore, the greater the benefit for improving health and the greater the opportunity to reduce the economic and societal burden of dementia. Key to knowing when and in whom to apply preventative interventions is the identification of at-risk individuals prior to the onset of age-related cognitive decline. Here, we view 'vulnerability' to poorer cognitive health in later life as not exclusively related to 'aging', but instead, to the accumulation of risks across the lifespan. This account predicts that some of the cognitive and brain differences evident in later life can be predicted by early life factors, and lends itself to the study of young healthy individuals who are at heightened risk of age-related cognitive decline via possession of genes associated with cognitive disorders of ageing. In this research proposal, we focus on the potential influence of one such common semi-dominant risk allele, APOE-e4, by asking: (a) whether healthy APOE-e4 carriers in early adulthood show selective brain and behavioural differences (compared to non-carriers) that are consistent with the early cognitive and anatomical markers of detrimental aging, and (b) how such early life effects may be moderated by cognitive reserve, gender and lifestyle factors.A large-scale neuroimaging study will be undertaken in young adults from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort, including novel application of 7T MRI which allows detailed assessment of key brain structures in the medial temporal lobe (e.g., hippocampus). This approach, which is founded on strong pilot evidence for early life brain network changes in young APOE e4 carriers (particularly during scene perception and memory) will identify the circumstances under which such cognitive changes in young at-risk individuals are seen, ask whether these brain network alterations are linked to behavioural performance (e.g., successful perception and memory), and determine how this early life cognitive vulnerability may be moderated by gender, lifestyle and cognitive reserve.